EA201790595A1 - Pyrimidinones as inhibitors of the XIA factor - Google Patents

Pyrimidinones as inhibitors of the XIA factor

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Publication number
EA201790595A1
EA201790595A1 EA201790595A EA201790595A EA201790595A1 EA 201790595 A1 EA201790595 A1 EA 201790595A1 EA 201790595 A EA201790595 A EA 201790595A EA 201790595 A EA201790595 A EA 201790595A EA 201790595 A1 EA201790595 A1 EA 201790595A1
Authority
EA
Eurasian Patent Office
Prior art keywords
inhibitors
compounds
pyrimidinones
xia factor
xia
Prior art date
Application number
EA201790595A
Other languages
Russian (ru)
Other versions
EA031590B1 (en
Inventor
Эндрю К. Дилгер
Джеймс Р. Корте
Индавати Дэ Лукка
Тианан Фан
Ву Ян
Юфен Ван
Кумар Балашанмуга Паббисетти
Уильям Р. Эвинг
Ехен Чжу
Рут Р. Векслер
Дональд Дж.П. Пинто
Майкл Дж. Орват
Леон М. Смит II
Original Assignee
Бристол-Маерс Сквибб Компани
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Бристол-Маерс Сквибб Компани filed Critical Бристол-Маерс Сквибб Компани
Publication of EA201790595A1 publication Critical patent/EA201790595A1/en
Publication of EA031590B1 publication Critical patent/EA031590B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Abstract

Настоящее изобретение предусматривает соединения формулы (I)или их стереомеры, таутомеры или фармацевтически приемлемые соли, где все переменные имеют значения, указанные в данной заявке, эти соединения являются селективными ингибиторами фактора XIa или двойными ингибиторами FXIa и плазменного калликреина. Данное изобретение относится также к фармацевтическим композициям, содержащим эти соединения, и к способам лечения тромбоэмболических осложнений и/или воспалительных заболеваний с их применением.The present invention provides compounds of formula (I) or stereomers, tautomers or pharmaceutically acceptable salts thereof, where all variables have the meanings indicated in this application, these compounds are selective inhibitors of factor XIa or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions containing these compounds, and to methods for treating thromboembolic complications and / or inflammatory diseases with their use.

EA201790595A 2014-10-01 2015-07-29 PYRIMIDINONES AS FACTOR XIa INHIBITORS EA031590B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201462058316P 2014-10-01 2014-10-01
PCT/US2015/042576 WO2016053455A1 (en) 2014-10-01 2015-07-29 Pyrimidinones as factor xia inhibitors

Publications (2)

Publication Number Publication Date
EA201790595A1 true EA201790595A1 (en) 2017-07-31
EA031590B1 EA031590B1 (en) 2019-01-31

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EA201790595A EA031590B1 (en) 2014-10-01 2015-07-29 PYRIMIDINONES AS FACTOR XIa INHIBITORS

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EP (4) EP4286372A3 (en)
JP (4) JP6462865B2 (en)
KR (2) KR102269999B1 (en)
CN (3) CN106795161B (en)
AR (1) AR101367A1 (en)
AU (3) AU2015324530B2 (en)
CA (1) CA2963395C (en)
CL (1) CL2017000712A1 (en)
CO (1) CO2017003833A2 (en)
CY (2) CY1119678T1 (en)
DK (2) DK3293186T3 (en)
EA (1) EA031590B1 (en)
ES (3) ES2655884T3 (en)
HR (2) HRP20171950T1 (en)
HU (2) HUE052812T2 (en)
IL (2) IL251434B (en)
LT (2) LT3089979T (en)
MA (1) MA40123A1 (en)
MX (2) MX2017003695A (en)
MY (1) MY183987A (en)
NO (1) NO2721243T3 (en)
NZ (2) NZ731416A (en)
PE (2) PE20210922A1 (en)
PH (2) PH12017500580B1 (en)
PL (1) PL3089979T3 (en)
PT (2) PT3293186T (en)
RS (2) RS61183B1 (en)
SG (2) SG11201702576QA (en)
SI (2) SI3089979T1 (en)
TN (2) TN2017000112A1 (en)
TW (2) TWI692478B (en)
UY (1) UY36244A (en)
WO (1) WO2016053455A1 (en)
ZA (1) ZA201702478B (en)

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NZ731416A (en) 2024-01-26
TW202043228A (en) 2020-12-01
ES2655884T3 (en) 2018-02-22
CN110734435B (en) 2022-06-07
MY183987A (en) 2021-03-17
TW201613923A (en) 2016-04-16
JP2017530157A (en) 2017-10-12
IL276470B (en) 2021-04-29
AU2020200376A1 (en) 2020-02-06
AU2021245098B2 (en) 2023-11-23
PH12017500580A1 (en) 2017-08-30
CA2963395C (en) 2023-03-14
JP2023134734A (en) 2023-09-27
AU2021245098A1 (en) 2021-10-28
JP2019069989A (en) 2019-05-09
JP6937734B2 (en) 2021-09-22
PE20170939A1 (en) 2017-07-13
TN2017000112A1 (en) 2018-07-04
NZ766570A (en) 2024-01-26
KR20180126612A (en) 2018-11-27
CO2017003833A2 (en) 2017-07-11
CY1119678T1 (en) 2018-04-04
PT3089979T (en) 2018-01-16
JP2021185182A (en) 2021-12-09
PH12020500195A1 (en) 2021-02-08
EA031590B1 (en) 2019-01-31
WO2016053455A1 (en) 2016-04-07
UY36244A (en) 2016-01-29
MX2017003695A (en) 2017-05-30
CN110734435A (en) 2020-01-31
MX2020010840A (en) 2020-11-06
AU2015324530B2 (en) 2019-10-24
SG11201702576QA (en) 2017-04-27
AU2015324530A1 (en) 2017-05-18
EP3828186B1 (en) 2023-08-23
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JP7317905B2 (en) 2023-07-31
AR101367A1 (en) 2016-12-14
IL251434A0 (en) 2017-05-29
LT3293186T (en) 2020-12-28
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KR102269999B1 (en) 2021-06-25
ES2963267T3 (en) 2024-03-26
MA40123A1 (en) 2017-09-29
KR101921436B1 (en) 2018-11-22
LT3089979T (en) 2017-12-27
EP3293186A1 (en) 2018-03-14
KR20170057431A (en) 2017-05-24
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PT3293186T (en) 2020-12-09
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CN114957255A (en) 2022-08-30
CL2017000712A1 (en) 2017-11-03
CN106795161B (en) 2019-10-15
RS61183B1 (en) 2021-01-29
HUE038061T2 (en) 2018-09-28
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